Our understanding of cancer initiation far exceeds our knowledge of tumor progression. The cell adhesion molecule E-cadherin contributes to aspects of tumor formation and invasion. The DNA-binding proteins Snail and Slug mediate E-cadherin transcriptional repression, and regulate aspects of carcinogenesis and cell survivability. While much has been learned regarding Snail and Slug biological function, the molecular mechanisms of Snail and Slug mediated transcriptional repression are not well understood. The studies in this proposal aim to determine the molecular mechanisms of Snail and Slug repression in the context of the E-cadherin promoter. First, specific activation of the E-cadherin promoter will be reconstituted in vitro, followed by biochemical studies to elucidate the mechanisms of Snail and Slug repression of E-cadherin. Finally, studies in vivo will be performed to complement the biochemical approaches, and examine E-cadherin transcriptional regulation in living cells. These studies will provide insight into the basis of Snail and Slug repression and E-cadherin silencing, and may potentially identify key components of tumor establishment and invasion.